Estrogen replacement therapy has been associated with reduction of cardiovascular events in postmenopausal women, although the mechanism of benefit is unknown. We undertook studies to determine the acute and chronic effects of estrogen administration on endothelium-dependent vasodilation in estrogen-deficient postmenopausal women. Thirty-three postmenopausal women, aged 59plus/minus7 years (meanplus/minusSD) participated in this study. The effects of estrogen administration on the forearm vascular responses to the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator sodium nitroprusside were studied during acute intra-arterial infusions of 5% dextrose solution and 17 beta-estradiol, and after 3 weeks of transdermal 17 beta-estradiol administration. Acute intra-arterial infusion of 17 beta-estradiol, which increased forearm venous estradiol levels from 16plus/minus11 to 345plus/minus202 pg/ml, potentiated the forearm vasodilation induced by acetylcholine by almost 50% compared to 5% dextrose but had minimal effect on the forearm vasodilation induced by sodium nitroprusside. However, after 3 weeks of transdermal estradiol administration (.1 mg patch every 3 days), achieving an estradiol level of 120plus/minus57 pg/ml, the vasodilator responses to acetylcholine and to sodium nitroprusside were unchanged from baseline. Repeat infusion of estradiol in 8 women, while on the patch, increased estradiol levels to 268plus/minus105 pg/ml and again potentiated the vasodilator response to acetylcholine to a similar degree to that observed in the baseline studies. Thus, we conclude that acute intra-arterial infusion of 17 beta-estradiol potentiates endothelium-dependent vasodilation in the forearms of postmenopausal women. However, this effect was not maintained with chronic (3 week), systemic estradiol administration. The different effects of acute and chronic estradiol may be due to the lower plasma levels achieved, the development of tolerance, or different cellular mechanisms of action with chronic administration.